Based on findings from the interim phase 1 portion of a trial examining ART4215 in combination with talazoparib in BRCA deficient breast cancer, a phase 2 portion will be initiated.
A phase 2 study (NCT04991480) evaluating the combination of ART4215 and talazoparib (Talzenna) has been initiated in an expansion study for the treatment of patients with BRCA deficient breast cancer, according to Artios Pharma Limited.1
ART4215 is a small molecule inhibitor of polymerase theta (Polθ) and talazoparib is an oral poly (ADP-ribose) polymerase (PARP) inhibitor. In preclinical studies, ART4215 has demonstrated broad potential clinical utility.
In the interim phase 1 part of the trial, tolerability and pharmacokinetic findings revealed ART4215 to be well tolerated. Based on these data, a recommended phase 2 dose has been established for ART4215 in combination with talazoparib. A randomized expansion cohort has also been initiated to examine the combination of ART4215 and talazoparib in patients with BRCA deficient breast cancer.
“Polθ is highly expressed in cancer cells, but has limited expression in healthy cells, making it an attractive cancer target. Initial phase 1 data supports a favorable tolerability profile and the potential for broad treatment use, particularly in combination with agents like PARP inhibitors where combinations with other DNA damage response inhibitors have been limited by toxicity,” said Niall Martin, MD, chief executive officer at Artios, in the press release. We are highly encouraged that ART4215 may offer a new treatment option that can synergize to overcome both de novo and acquired PARP resistance. We look forward to reporting phase 1 safety and tolerability data in the first half of 2023.”
The ongoing, first-in-human, global, open-label phase 1/2 study of ART4215 is currently being investigated to assess the safety, tolerability, pharmacokinetics, and clinical activity of ART4215 as a monotherapy or in combination with talazoparib in patients with advanced or metastatic solid tumors.2
Up to 206 patients aged 18 years and older will be enrolled in the trial which will be conducted at multiple locations across the United States and Europe.
All patients must have discontinued all prior treatments for cancer for at least 21 days or 5 half-lives and recovered from the acute effects of therapy to be included in the trial. Patients must have at least 1 radiologically evaluable lesion, acceptable hematologic, renal, hepatic, and coagulation functions, and an estimated life expectancy of ≥ 12 weeks.
For part A, patients must have advanced or metastatic cancer, which is refractory to standard therapies, or for which no standard therapies exist, and non-irradiated tumor tissue samples available for submission for analysis. For part A2, patients enrolled will be those with advanced or metastatic cancer for which a PARP inhibitor is an appropriate treatment option and optional baseline biopsy for BRCA1/2 mutations and prior PARP inhibitor. Patients in part B must have advanced or metastatic solid tumors that have undergone disease progression during treatment with a PARP inhibitor for an approved indication, at least 1 measurable lesion assessable using standard techniques by RECIST v1.1 or PCWG-3 guidelines, and non-irradiated, biopsiable tumor lesion.
Patients enrolled in part B2 must have advanced or metastatic cancer that is refractory to standard therapies, or for which no standard therapies exist, no prior treatment with a PARP inhibitor and must not have a disease for which there is an approved PARP inhibitor, and at least 1 measurable lesion assessable using standard techniques by RECIST v1.1 or PCWG-3 guidelines, and patients in part B3 are required to have HER2-negative locally advanced or metastatic breast cancer with no deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation, no more than 3 prior chemotherapy-inclusive regimens, prior treatment with a taxane or anthracycline unless contraindicated, no prior treatment with a PARP inhibitor, and at least 1 measurable lesion assessable using standard techniques by RECIST v1.1.
Those enrolled in parts A1, B1, and B2 of the trial will receive ART4215 alone orally and daily in 21-day cycles. In part A2, patients will receive oral ART4215 daily in 21-day cycles in combination with talazoparib orally administered at a dose of 1 mg or 0.75 mg in 21-day cycles. In part B3, approximately 120 participants with HER2 negative BRCA breast cancers will be randomized in a 1:1 ratio to receive either ART4215 in combination with talazoparib or talazoparib alone. Lastly, part A3 will examine the combination of ART4215 and niraparib in 21-day cycles in up to 30 participants.
The primary end point for part A is the number of participants with dose limiting toxicities from ART4215 monotherapy, in combination with talazoparib or in combination with niraparib while it is the number of participants with adverse events following administration of ART4215 in part B1 and B2. Then in part B3, the primary end point is progression-free survival (PFS) as a measure of efficacy for ART4215 in combination with talazoparib or talazoparib alone.
In part A, B1, and B2, the secondary end points consist of PFS, overall survival, and pharmacokinetics. The secondary end points for part A2 are pharmacokinetics and assessment of lesions in DNA repair pathways by immunohistochemistry for loss of shielding complex and/or TP53BP1 or other relevant pathways. For part B3, secondary end points include number of participants with adverse events following administration of the combination, best overall response, objective response rate, disease control rate, duration of response, and change in tumor size as a measure of efficacy.
“Patients with advanced solid tumors have achieved improved outcomes with the development of PARP inhibitors. However, there is still a need to address resistance mechanisms diminishing initial tumor responses and leading to disease progression. ART4215 has the potential to help overcome these limitations, and we are excited that the initiation of this phase 2 trial represents an important step in the clinical evaluation of Polθ as a novel target,” said Erika P. Hamilton, MD, lead study investigator, director of the breast cancer and gynecologic cancer research program, Sarah Cannon Research Institute at Tennessee Oncology, in a press release.